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Cancer drug hints at treatment for bipolar disorder

By Roxanne Khamsi

The breast cancer drug tamoxifen has shown surprising success in treating the manic episodes that patients with bipolar disorder suffer. Researchers say that the results from their pilot study offer hope that they will be able to design a new class of drugs to treat this mental illness, though doing so will take time.

“This is definitely something to get excited about in the sense that it’s a novel approach,” comments Rif El-Mallakh, a mood disorder researcher at the University of Louisville, Kentucky, US who was not involved with the new study.

Some experts suggest that more than 5 million Americans suffer from some form of bipolar disorder, a condition marked by alternating periods of severe depression and mania. And a recent report found a 40-fold increase in this mental illness from 1994 to 2003 – though many people suspect this might be a result of overdiagnosis.

Those affected by bipolar disorder often take excessive risks and become hyperactive when they experience a manic episode. “Mania destroys people’s lives,” according El-Mallakh. For example, in one episode an otherwise faithful husband invited women into his house to try on his wife’s lingerie, El Mallakh says. Another patient who had very little money made the irrational decision of using his disability cheque to make a down payment on a desirable new car.

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Toxic medication

In bipolar disorder, the highs of a manic episode might be immediately followed by a period of deep depression, and this can put people at greater risk of suicide, explains Jack Akester of the patient advocacy group Mental Health America, which is based in Alexandria, Virginia, US.

But the drugs given to patients experiencing a manic episode, such as lithium, do not always prove effective. “We have lithium, which treats the manic phase, but it has a certain amount of toxicity” that can negatively affect organs such as the liver, says Akester.

Post-mortem exams have found above-average amounts of a type of molecule known as protein kinase C (PKC) in the brain cells of patients with bipolar disorder. Among its many functions, PKC activates receptors on the outside of brain cells, modifying how well they receive signals.

Scientists such as Husseini Manji at the National Institutes of Mental Health in Bethesda, Maryland, US, suspect that excessive influence by PKC might disrupt communication between brain cells and thereby contribute to bipolar disorder. So Manji and his colleagues recruited 16 patients experiencing manic episodes and gave half of them daily doses of tamoxifen – which inhibits the action of PKC.

Drug target

While 63% of the patients who received tamoxifen had reduced manic symptoms during the three week trial, only 13% of their control counterparts given a placebo showed this improvement. And the tamoxifen appeared to have this impact quickly – within five days. By comparison, current drugs to treat manic episodes generally take at least a week to produce an effect.

Experts stress that tamoxifen itself should not be used as a treatment for bipolar disorder as it interferes with the hormone oestrogen. The drug can cause early menopause, for example.

Instead, they suggest that drug developers focus their efforts on other compounds that can inhibit PKC without influencing oestrogen signalling in the body. Manji points to one potent inhibitor of PKC – chelerythrine – that is still in early stages of testing, and has not yet received regulatory approval.

He adds that PKC molecules work throughout the body, so scientists should try to develop drugs that can specifically inhibit the forms of PKC found in the brain. “PKC has a lot of different functions that you wouldn’t want to hit with a sledgehammer,” says Manji.